U.S. patent number 10,745,350 [Application Number 15/748,827] was granted by the patent office on 2020-08-18 for compounds and pharmaceutical composition associated with ubiquitination-proteasome system.
This patent grant is currently assigned to Calgent Biotechnology Co., Ltd.. The grantee listed for this patent is CALGENT BIOTECHNOLOGY CO., LTD.. Invention is credited to Jing-ping Liou, Shiow-lin Pan, Yun Yen.
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United States Patent |
10,745,350 |
Yen , et al. |
August 18, 2020 |
Compounds and pharmaceutical composition associated with
ubiquitination-proteasome system
Abstract
The invention relates to new compounds with low cytotoxicity for
blocking ubiquitination-proteasome system in diseases. Accordingly,
these compounds can be used in treatment of treating disorders
including, but not limited to, cancers, neurodegenerative diseases,
inflammatory disorders and autoimmune disorders and metabolic
disorders.
Inventors: |
Yen; Yun (Arcadia, CA),
Liou; Jing-ping (Taipei, TW), Pan; Shiow-lin
(Taipei, TW) |
Applicant: |
Name |
City |
State |
Country |
Type |
CALGENT BIOTECHNOLOGY CO., LTD. |
Taipei |
N/A |
TW |
|
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Assignee: |
Calgent Biotechnology Co., Ltd.
(Taipei, TW)
|
Family
ID: |
57885556 |
Appl.
No.: |
15/748,827 |
Filed: |
July 30, 2016 |
PCT
Filed: |
July 30, 2016 |
PCT No.: |
PCT/US2016/044932 |
371(c)(1),(2),(4) Date: |
January 30, 2018 |
PCT
Pub. No.: |
WO2017/020030 |
PCT
Pub. Date: |
February 02, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190144383 A1 |
May 16, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62199207 |
Jul 30, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/7048 (20130101); A61K 31/40 (20130101); A61K
33/24 (20130101); A61K 45/06 (20130101); C07D
209/08 (20130101); C07D 209/44 (20130101); C07C
255/58 (20130101); A61P 25/14 (20180101); C07D
213/40 (20130101); C07D 207/04 (20130101); C07C
311/29 (20130101); A61P 25/28 (20180101); C07C
235/54 (20130101); C07C 237/34 (20130101); A61K
31/166 (20130101); C07D 215/40 (20130101); C07D
295/135 (20130101); C07D 295/13 (20130101); C07C
225/30 (20130101); A61P 35/00 (20180101); C07D
215/38 (20130101); A61P 3/10 (20180101); A61K
31/122 (20130101); C07C 237/48 (20130101); A61K
31/166 (20130101); A61K 2300/00 (20130101); A61K
31/40 (20130101); A61K 2300/00 (20130101); A61K
31/122 (20130101); A61K 2300/00 (20130101); A61K
31/7048 (20130101); A61K 2300/00 (20130101); A61K
33/24 (20130101); A61K 2300/00 (20130101); C07C
2602/10 (20170501) |
Current International
Class: |
A61K
31/122 (20060101); A61K 31/70 (20060101); C07D
207/04 (20060101); A61K 45/06 (20060101); A61P
35/00 (20060101); C07D 295/135 (20060101); C07D
295/13 (20060101); C07C 311/29 (20060101); C07C
237/34 (20060101); C07C 237/48 (20060101); C07C
225/30 (20060101); C07C 255/58 (20060101); C07D
209/08 (20060101); C07D 209/44 (20060101); C07D
215/38 (20060101); C07D 215/40 (20060101); A61K
33/24 (20190101); A61K 31/7048 (20060101); C07C
235/54 (20060101); A61P 3/10 (20060101); A61P
25/28 (20060101); A61P 25/14 (20060101); A61K
31/166 (20060101); A61K 31/40 (20060101); C07D
213/40 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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20180526 |
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Feb 2018 |
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TW |
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2010/005534 |
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Jan 2010 |
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WO |
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2011/017519 |
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Feb 2011 |
|
WO |
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2014/201016 |
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Dec 2014 |
|
WO |
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2017/020030 |
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Feb 2017 |
|
WO |
|
Other References
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naphthoquinone analogs as a novel class of proteasome inhibitors.
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examiner .
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(1977), 66, 1-19. cited by applicant .
Chang L, et al. "The E3 ubiguitin ligase itch couples JNK
activation to TNFalpha-induced cell death by inducing c-FLIP(L)
turnover", Cell. Feb. 10, 2006;124(3):601-13. cited by applicant
.
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Co., Easton, Pa. 1990. cited by applicant .
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lysine-63 linkages", Biochem Pharmacol. Dec. 1, 2008;
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105124708 (Publication No. TW 20180526 A). The cited references in
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of naphthoquinone analogs as a novel class of proteasome
inhibitors." Bioorganic & Medicinal Chemistry 18.15 (2010):
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as antiproliferative agents and 20S proteasome inhibitors."
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dated Feb. 11, 2020, in 5 pages. cited by applicant .
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3-Chloro-l,4-naphthoquinone Derivatives", Bioorganic &
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QSAR study of 1,4-naphthoquinone derivatives", European Journal of
Medicinal Chemistry, 2014, vol. 84, pp. 247-263. cited by applicant
.
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substituted 1,4-naphthoquinones", Bioorganic & Medicinal
Chemistry 2013, vol. 21, No. 15, pp. 4662-4669. cited by applicant
.
Oliveira, M. F. et al., "New enamine derivatives of lapachol and
biological activity", Anais da Academia Brasileira de Ciencias,
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Phutdawong, W. et al., "Synthesis and Anticancer Activity of
5,6,8,13-tetrahydro-7Hnaphtho[2,3-a][3]-benzazepine-8,13-diones",
Archives of Pharmacal Research, 2012, vol. 35, No. 5, pp. 769-777.
cited by applicant .
Francisco, A. I. et al., "Novel
2-(R-phenyl)amino-3-(2-methylpropenyl)-[1,4]-naphthoquinones:
Synthesis, Characterization, Electrochemical Behavior and Antitumor
Activity", Journal of the Brazilian Chemical Society, 2010, vol.
21, No. 1, pp. 169-178. cited by applicant .
Hsu, T-S. et al., "7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione
(PT-262), a novel synthetic compound induces lung carcinoma cell
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|
Primary Examiner: Shterengarts; Samantha L
Attorney, Agent or Firm: Prosyla Group PC
Claims
What is claimed is:
1. A compound having the following Formula (I): ##STR00065##
wherein R.sub.1 is halogen, alkyl, alkenyl, alkynyl, NH.sub.2,
NO.sub.2, OH or CN; each R.sub.2 is the same or different,
representing H, alkyl, C.sub.2-10 alkenyl, alkynyl, NH.sub.2,
NO.sub.2, C.sub.1-10 alkyloxy, alkylthio, alkylamino,
alkyloxyalkyl, OH or CN, aryl or heterocyclic having 1 to 3
heteroatoms selected from the group consisting of N, O and S;
R.sub.3 is H, alkyl, alkenyl, alkynyl, NH.sub.2, NO.sub.2, OH or
CN; R.sub.4 is H, alkyl, alkenyl, alkynyl, NH.sub.2, NO.sub.2, OH
or CN, or R.sub.4 together with nitrogen atom attached therefrom
and R.sub.5 form a fused bicyclic ring having 0 to 3 heteroatoms
selected from O; N and S; R.sub.5 is alkylene-R.sub.6 wherein
R.sub.6 is OH, NO.sub.2, CN, alkyl, alkenyl, alkynyl,
NR.sub.aR.sub.b, cycloalkyl, aryl, heterocyclic ring having 0 to 3
heteroatoms selected from O; N and S or fused heterocyclic ring
having 0 to 3 heteroatoms selected from O, N and S, each of
cycloalkyl, aryl, heterocyclic ring and fused heterocyclic ring is
unsubstituted or substituted with one to three of OH; halogen;
NH.sub.2; NO.sub.2, CN, alkyl; alkenyl; alkynyl; alkyloxy;
heteroaryl having 1 to 3 heteroatoms selected from the group
consisting of N, O and S, unsubstituted or substituted with alkyl,
alkenyl, alkynyl, OH, halogen, CN, NH.sub.2 or NO.sub.2; and
R.sub.a and R.sub.b are the same or different, independently
representing H; OH; alkyl; alkenyl; alkynyl; alkyloxy; cycloalkyl;
heterocyclyl; alkyleneamino; alkylene-N-(alkyl).sub.2; aryl
unsubstituted or substituted with OH, halogen, CN, NH.sub.2,
NO.sub.2, alkyl, alkenyl, alkynyl, alkyloxy or heteroaryl,
heteroaryl unsubstituted or substituted with OH, halogen, CN,
NH.sub.2, NO.sub.2, alkyl, alkenyl, alkynyl or alkyloxy;
alkylene-heteroaryl; or alkylene-heterocyclyl unsubstituted or
substituted with alkyl; X is --C(O), --S(O).sub.2-- or
--NH--C(O)--; m is an integer of 0-3; and n is an integer of 1-7;
or a tautomer or stereoisomer thereof, or a solvate, prodrug or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein m is 0; R.sub.1 is halogen; n
is any integer of 1-4; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is alkylene-R.sub.6 wherein R.sub.6 is NR.sub.aR.sub.b,
C.sub.5-7 heterocyclic ring having 0 to 3 hetero atoms selected
from O, N and S; or C.sub.10-12 fused heterocyclic ring having 0 to
3 hetero selected from O, N and S; and R.sub.a and R.sub.b are
alkyl.
3. The compound of claim 1, wherein m is 0; R.sub.1 is halogen; n
is any integer of 1-2; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is (CH.sub.2).sub.1-4R.sub.6 wherein R.sub.6 is
unsubstituted or substituted pyrrolidinyl, oxolanyl, thiolanyl,
pyrrolyl, furanyl, thiophenyl, piperidinyl, oxanyl, thianyl,
morpholinyl, pyridinyl, piperidinyl, piperazinyl, thiopyranyl,
pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl; benzimidazolyl;
pyrazolyl; indazolyl; pyrazolyl; quinolinyl; indolyl; indazolyl;
azaindolyl; azaindazolyl; deazapurinyl; or indanyl.
4. The compound of claim 1, wherein m is 0; R.sub.1 is halogen; n
is any integer of 1-2; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is (CH.sub.2).sub.1-4R.sub.6 wherein R.sub.6 is
unsubstituted or substituted pyrrolidinyl, morpholinyl, pyridinyl,
piperidinyl, piperazinyl, or indolyl.
5. The compound of claim 1, wherein m is 0; R.sub.1 is Cl; n is 1;
R.sub.3 is H, x is C(O); R.sub.4 is H; R.sub.5 is
CH.sub.2CH.sub.2N(CH.sub.3).sub.2, pyrrolidinyl substituted by
ethyl, or CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2.
6. The compound of claim 1, wherein the compound is selected from
the group consisting of: ##STR00066## or a tautomer or stereoisomer
thereof, or a solvate, prodrug or a pharmaceutically acceptable
salt thereof.
7. A pharmaceutical composition, comprising a compound of any of
claim 1 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7, further comprising a
second therapeutic agent.
9. The pharmaceutical composition of claim 8, wherein the second
therapeutic agent is selected from a mitotic inhibitor, vinca
alkaloids and vepesid; an anthracycline antibiotic; a nucleoside
analog; an EGFR inhibitor; an folate antimetabolite; cisplatin,
carboplatin or a HDAC inhibitor.
10. The pharmaceutical composition of claim 8, wherein the second
therapeutic agent is a corticosteroid, a lubricant, a keratolytic
agent, a vitamin D.sub.3 derivative, PUVA and anthralin,
.beta..sub.2-agonist, a corticosteroid, immunosuppressant, NSAID,
COX-2 inhibitor, biologic, non-steroidal calcineurin inhibitor,
steroidal anti-inflammatory agent, 5-amino salicylic acid, DMARDs,
hydroxychloroquine sulfate, inflammatory modulator, agents that
interferes with B cell action or penicillamine.
11. The pharmaceutical composition of claim 9, wherein the mitotic
inhibitor is a taxane.
12. The pharmaceutical composition of claim 11, wherein the taxane
is selected from paclitaxel or docetaxel.
13. The pharmaceutical composition of claim 9, wherein the vinca
alkaloid is selected from vinblastine, vincristine, vindesine or
vinorelbine.
14. The pharmaceutical composition of claim 9, wherein the
antracycline antibiotic is selected from doxorubicin, daunorubicin,
daunorubicin, epirubicin, idarubicin, valrubicin or
mitoxantrone.
15. The pharmaceutical composition of claim 9, wherein the
nucleoside analog is gemcitabine.
16. The pharmaceutical composition of claim 9, wherein the EGFR
inhibitor is selected from gefitinib or erlotinib.
17. The pharmaceutical composition of claim 9, wherein the folate
antimetabolite is selected from trimethoprim, pyrimethamine or
pemetrexed.
Description
FIELD OF THE INVENTION
The present invention relates to the identification of new drug
targets for therapy of disorders. In particular, the present
invention relates to new drug targets with low cytotoxicity for
blocking the ubiquitination-proteasome system in diseases.
BACKGROUND OF THE INVENTION
Cancer is a disease in which cells in the body grow out of control.
The majority of the current cancer treatment methods result in
severe general toxicity to the human body. Both radiation and
chemotherapy have deleterious effects to the host, causing
significant morbidity and mortality. Hence, there is a need in the
art for non-invasive and non-toxic methods of treating cancer and
preventing tumor growth. However, the cancer cannot be effectively
cured. Therefore, there is a need to develop a compound effectively
treating a cancer but having low cytotoxicity.
Inflammation is a mechanism that protects mammals from invading
pathogens. However, while transient inflammation is necessary to
protect a mammal from infection, uncontrolled inflammation causes
tissue damage and is the underlying cause of many illnesses.
Inflammation is typically initiated by binding of an antigen to
T-cell antigen receptor. Antigen binding by a T-cell initiates
calcium influx into the cell via calcium ion channels, such as
Ca.sup.2+-release-activated Ca' channels (CRAC). Calcium ion influx
in turn initiates a signaling cascade that leads to activation of
these cells and an inflammatory response characterized by cytokine
production. Over production of proinflammatory cytokines other than
IL-2 has also been implicated in many autoimmune diseases.
Therefore, there is a continuing need for new drugs which overcome
one or more of the shortcomings of drugs currently used for the
treatment or prevention of inflammatory disorders, allergic
disorders and autoimmune disorders.
Proteasomes are part of a major mechanism by which cells regulate
the concentration of particular proteins and degrade misfolded
proteins. Proteasomes are large ring- or cylinder-shaped
multicomponent complexes common to all eukaryotic cells.
Proteasomes are large multi-subunit protease complexes, localized
in the nucleus and cytosol, which selectively degrade intracellular
proteins. Proteasomes play a major role in the degradation of many
proteins that are involved in cell cycling, proliferation, and
apoptosis. They have at least three distinct endopeptidase
activities which include hydrolysis of peptide bonds on the
carboxyl side of hydrophobic, basic, and acidic amino acid
residues. Proteasomes, through their protein degradation activity,
have been implicated in several important cell functions, including
DNA repair, cell cycle progression, signal transduction,
transcription, and antigen presentation.
Proteasome inhibition represents an important new strategy in
cancer treatment.
U.S. Pat. Nos. 7,442,830, 8,003,819 and 8,058,262 relate to boronic
acid and boronic ester compounds useful as proteasome inhibitors.
U.S. Pat. No. 8,389,564 provides salinosporamide used to treating
and/or ameliorating a disease or condition, such as cancer, a
microbial disease and/or inflammation. WO 2010/005534 provides
compounds having activity as inhibitors of proteasomes.
However, there is an ongoing need for new and/or improved
inhibitors of proteasome.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. The compounds of the invention blocks ITCH
self-ubiquitnation (Lys-dependent) more efficiently than the
control compound.
SUMMARY OF THE INVENTION
One aspect of the invention is to provide a compound having the
following Formula (I):
##STR00001##
Another aspect of the invention is to provide a compounds having
the following Formula (II):
##STR00002##
Another aspect of the invention is to provide a pharmaceutical
composition containing a compound of Formula (I) or Formula
(II).
A further aspect is to provide a method for inhibiting ITCH E3
ligase, comprising administrating a compound of Formula (I) or
Formula (II) to a cell or a subject.
Another further aspect is to provide a method for treating a
cancer, comprising administrating a compound of Formula (I) or
Formula (II) to a cell or a subject.
Another further aspect is to provide a method for treating
autoimmune disorders, comprising administrating a compound of
Formula (I) or Formula (II) to a cell or a subject.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to new compounds with low cytotoxicity for
blocking the ubiquitination-proteasome system in diseases.
Accordingly, these compounds can be used to treat disorders
including, but not limited to, cancers, inflammatory disorders and
autoimmune disorders.
Definitions and Terms
Terms not specifically defined herein should be understood
according to the meanings that would be given to them by one of
skill in the art in light of the disclosure and the context. As
used in the specification, however, unless specified to the
contrary, the following terms have the meaning indicated according
to the following conventions.
The terms "a" and "an" refer to one or more.
The terms "disease" and "disorder" herein can be used
interchangeably.
The terms "treatment" and "treating" embrace both preventative,
i.e. prophylactic, or therapeutic, i.e. curative and/or palliative,
treatment. Thus the terms "treatment" and "treating" comprise
therapeutic treatment of patients having already developed said
condition, in particular in manifest form. Therapeutic treatment
may be symptomatic treatment in order to relieve the symptoms of
the specific indication or causal treatment in order to reverse or
partially reverse the conditions of the indication or to stop or
slow down progression of the disease. Thus the compounds,
compositions and methods of the present invention may be used for
instance as therapeutic treatment over a period of time as well as
for chronic therapy. In addition the terms "treatment" and
"treating" comprise prophylactic treatment, i.e. a treatment of
patients at risk to develop a condition mentioned hereinbefore,
thus reducing said risk.
The term "therapeutically effective amount" means an amount of a
compound of the present invention that (i) treats or prevents the
particular disease or condition, (ii) attenuates, ameliorates, or
eliminates one or more symptoms of the particular disease or
condition, or (iii) prevents or delays the onset of one or more
symptoms of the particular disease or condition described
herein.
The term "substituted" as used herein, means that any one or more
hydrogens on the designated atom, radical or moiety is replaced
with a selection from the indicated group, provided that the atom's
normal valence is not exceeded, and that the substitution results
in an acceptably stable compound.
The term"pharmaceutically acceptable" is employed herein to refer
to those compounds, materials, compositions, and/or dosage forms
which are, within the scope of medical judgment, suitable for use
in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, and commensurate with a reasonable benefit/risk
ratio.
As used herein, "pharmaceutically acceptable salts" refers to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines,
pyridine, pyrimidine and quinazoline; alkali or organic salts of
acidic residues such as carboxylic acids; and the like.
As used herein, the term "stereoisomer" is a general term for all
isomers of individual molecules that differ only in the orientation
of their atoms in space. It includes enantiomers and isomers of
compounds with more than one chiral center that are not mirror
images of one another (diastereoisomers).
The term "chiral center" refers to a carbon atom to which four
different groups are attached.
The terms "enantiomer" and "enantiomeric" refer to a molecule that
cannot be superimposed on its mirror image and hence is optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image compound rotates the plane of
polarized light in the opposite direction.
The term "racemic" refers to a mixture of equal parts of
enantiomers that is optically inactive.
The term "resolution" refers to the separation or concentration or
depletion of one of the two enantiomeric forms of a molecule.
As used herein, halo or halogen refers to fluoro, chloro, bromo or
iodo.
As used herein, the term "alkyl" refers to straight or branched
hydrocarbon chains containing the specified number of carbon atoms.
For example, "C.sub.1-C.sub.6 alkyl" is selected from
straight-chained and branched non-cyclic hydrocarbons having from 1
to 6 carbon atoms. Representative straight chain C.sub.1-C.sub.6
alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl,
-n-pentyl, and -n-hexyl. Representative branched C.sub.1-C.sub.6
alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,
-isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,
2,3-dimethylbutyl, and 3,3-dimethylbutyl.
As used herein, the term "alkenyl" refers to straight or branched
chain hydrocarbon chains containing the specified number of carbon
atoms and one or more double bonds. For example, "C.sub.2-C.sub.6
alkenyl" is selected from straight chain and branched non-cyclic
hydrocarbons having from 2 to 6 carbon atoms and including at least
one carbon-carbon double bond. Representative straight chain and
branched C.sub.2-C.sub.6 alkenyl groups include -vinyl, -allyl,
-1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl,
-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,
-1-hexenyl, 2-hexenyl, and 3-hexenyl.
As used herein, a "C.sub.2-C.sub.6 alkynyl" is selected from
straight chain and branched non-cyclic hydrocarbon having from 2 to
6 carbon atoms and including at least one carbon-carbon triple
bond. Representative straight chain and branched C.sub.2-C.sub.6
alkynyl groups include -acetylenyl, -propynyl, -1-butyryl,
-2-butyryl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl,
-4-pentynyl, -1-hexynyl, -2-hexynyl, and -5-hexynyl.
The term "C.sub.1-n-alkylene" wherein n is an integer 1 to n,
either alone or in combination with another radical, denotes an
acyclic, straight or branched chain divalent alkyl radical
containing from 1 to n carbon atoms. For example the term
C.sub.1-4-alkylene includes --(CH.sub.2)--,
--(CH.sub.2--CH.sub.2)--, --(CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2)--, --(C(CH.sub.3).sub.2)--,
--(CH(CH.sub.2CH.sub.3))--, --(CH(CH.sub.3)--CH.sub.2)--,
--(CH.sub.2--CH(CH.sub.3))--,
--(CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH.sub.2--CH(CH.sub.3))--,
--(CH(CH.sub.3)--CH.sub.2--CH.sub.2)--,
--(CH.sub.2--CH(CH.sub.3)--CH.sub.2)--,
--(CH.sub.2--C(CH.sub.3).sub.2)--,
--(C(CH.sub.3).sub.2--CH.sub.2)--,
--(CH(CH.sub.3)--CH(CH.sub.3))--,
--(CH.sub.2--CH(CH.sub.2CH.sub.3))--,
--(CH(CH.sub.2CH.sub.3)--CH.sub.2)--,
--(CH(CH.sub.2CH.sub.2CH.sub.3))--, --(CHCH(CH.sub.3).sub.2)-- and
--C(CH.sub.3)(CH.sub.2CH.sub.3)--.
As used herein, "cycloalkyl" refers to a group selected from
C.sub.3-C.sub.12 cycloalkyl, and preferably a C.sub.3-8 cycloalkyl.
Typical cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
cyclononyl.
As used herein, the term "heterocyclyl" refers to groups containing
one to four heteroatoms each selected from O, S and N, wherein each
heterocyclic group has from 4 to 10 atoms in its ring system, and
wherein the ring of said group does not contain two adjacent O or S
atoms. Typical heterocyclyl groups include pyrrolidinyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, sulfolanyl, morpholino, thiomorpholino, thioxanyl,
piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, dihydroquinazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,
3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl.
As used herein, the term "alkoxy" refers to a straight or branched
alkoxy group containing the specified number of carbon atoms. For
example, C.sub.1-6alkoxy means a straight or branched alkoxy group
containing at least 1, and at most 6, carbon atoms. Examples of
"alkoxy" as used herein include, but are not limited to, methoxy,
ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy,
2-methylprop-2-oxy, pentoxy and hexyloxy. The point of attachment
may be on the oxygen or carbon atom.
As used herein, the term "alkylthio (also termed as alkylsulfanyl)
refers to straight-chain or branched alkyl groups (preferably
having 1 to 6 carbon atoms, e.g. 1 to 4 carbon atoms
(C.sub.1-C.sub.6-alkylthio), which are bound to the remainder of
the molecule via a sulfur atom at any bond in the alkyl group.
Examples of C.sub.1-C.sub.4-alkylthio include methylthio,
ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio,
isobutylthio and tert-butylthio. Examples of
C.sub.1-C.sub.6-alkylthio include, apart from those mentioned for
C.sub.1-C.sub.4-alkylthio, 1-, 2- and 3-pentylthio, 1-, 2- and
3-hexylthio and the positional isomers thereof.
As used herein, the term "alkoxyalkyl" refers to the group
-alk.sub.1-O-alk.sub.2 where alk.sub.1 is alkyl or alkenyl, and
alk.sub.2 is alkyl or alkenyl.
As used herein, the term "alkylamino" refers to the group --NRR'
where R is alkyl and R' is hydrogen or alkyl.
As used herein, "aryl" refers to a group selected from C.sub.6-14
aryl, especially C.sub.6-10 aryl. Typical C.sub.6-14 aryl groups
include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,
azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
As used herein, "heteroaryl" refers to a group having from 5 to 14
ring atoms; 6, 10 or 14 pi electrons shared in a cyclic array; and
containing carbon atoms and 1, 2 or 3 oxygen, nitrogen and/or
sulfur heteroatoms. Examples of heteroaryl groups include
indazolyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, azepinyl,
oxazepinyl, morpholinyl, thiazepinyl, diazepinyl, thiazolinyl,
benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl,
benzothiazinyl, benzothiophenyl oxazolopyridinyl, benzofuranyl,
quinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl,
phthalimido, benzofuranyl, benzodiazepinyl, indolyl, indanyl,
azaindazolyl, deazapurinyl and isoindolyl.
As used herein, the term "amino" or "amino group" refers to
--NH.sub.2.
As used herein, the term "optionally substituted" refers to a group
that is unsubstituted or substituted with one or more substituents.
For example, where the groups C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
--O--C.sub.1-C.sub.6 alkyl, --O--C.sub.2-C.sub.6 alkenyl, and
--O--C.sub.2-C.sub.5 alkynyl are referred to as being optionally
substituted, they may or may not be substituted. Where substituted,
they may be substituted with a group selected from the group
consisting of halo, halo(C.sub.1-6)alkyl,
(halo).sub.2(C.sub.1-6)alkyl, (halo).sub.3(C.sub.1-6)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, aryl(C.sub.1-6)alkyl,
aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl,
cycloalkyl(C.sub.1-6)alkyl, heterocyclo(C.sub.1-6)alkyl,
hydroxyl(C.sub.1-6)alkyl, amino(C.sub.1-6)alkyl,
carboxy(C.sub.1-6)alkyl, alkoxy(C.sub.1-6)alkyl, nitro, amino,
ureido, cyano, alkylcarbonylamino, hydroxyl, thiol,
alkylcarbonyloxy, azido, alkoxy, carboxy, aminocarbonyl, and
C.sub.1-6alkylthiol. Preferred optional substituents include halo,
halo(C.sub.1-6)alkyl, (halo).sub.2(C.sub.1-6)alkyl,
(halo).sub.3(C.sub.1-6)alkyl, hydroxyl(C.sub.1-6)alkyl,
amino(C.sub.1-6)alkyl, hydroxyl, nitro, C.sub.1-6alkyl,
C.sub.1-6alkoxy and amino. Preferred numbers of optional
substituents are 1, 2 or 3.
Compounds of the Invention or a Tautomer or Stereoisomer Thereof,
or a Solvate, Prodrug or a Pharmaceutically Acceptable Salt
Thereof
In one aspect, the invention provides a compound having the
following Formula (I):
##STR00003## wherein R.sub.1 is halogen, alkyl, alkenyl, alkynyl,
NH.sub.2, NO.sub.2, OH or CN; each R.sub.2 is the same or
different, representing H, alkyl, C.sub.2-10alkenyl, alkynyl,
NH.sub.2, NO.sub.2, C.sub.1-10alkyloxy, alkylthio, alkylamino,
alkyloxyalkyl, OH or CN, aryl or heterocyclic having 1 to 3
heteroatoms selected from the group consisting of N, O and S;
R.sub.3 is H, alkyl, alkenyl, alkynyl, NH.sub.2, NO.sub.2, OH or
CN; R.sub.4 is H, alkyl, alkenyl, alkynyl, NH.sub.2, NO.sub.2, OH
or CN, or R.sub.4 together with nitrogen atom attached therefrom
and R.sub.5 form a fused bicyclic ring having 0 to 3 heteroatoms
selected from O; N and S; R.sub.5 is alkylene-R.sub.6 wherein
R.sub.6 is OH, NO.sub.2, CN, alkyl, alkenyl, alkynyl,
NR.sub.aR.sub.b, cycloalkyl, aryl, heterocyclic ring having 0 to 3
heteroatoms selected from O; N and S or fused heterocyclic ring
having 0 to 3 hetero atoms selected from O, N and S, each of
cycloalkyl, aryl, heterocyclic ring and fused heterocyclic ring is
unsubstituted or substituted with one to three of OH; halogen;
NH.sub.2; NO.sub.2, CN, alkyl; alkenyl; alkynyl; alkyloxy;
heteroaryl having 1 to 3 heteroatoms selected from the group
consisting of N, O and S, unsubstituted or substituted with alkyl,
alkenyl, alkynyl, OH, halogen, CN, NH.sub.2 or NO.sub.2; and
R.sub.a and R.sub.b are the same or different, independently
representing H; OH; alkyl; alkenyl; alkynyl; alkyloxy; cycloalkyl;
heterocyclyl; alkyleneamino; alkylene-N-(alkyl).sub.2; aryl
unsubstituted or substituted with OH, halogen, CN, NH.sub.2,
NO.sub.2, alkyl, alkenyl, alkynyl, alkyloxy or heteroaryl;
heteroaryl unsubstituted or substituted with OH, halogen, CN,
NH.sub.2, NO.sub.2, alkyl, alkenyl, alkynyl or alkyloxy;
alkylene-heteroaryl; or alkylene-heterocyclyl unsubstituted or
substituted with alkyl; X is --C(O), --S(O).sub.2 or --NH--C(O)--;
m is an integer of 0-3; and n is an integer of 0-7; or a tautomer
or stereoisomer thereof, or a solvate, prodrug or a
pharmaceutically acceptable salt thereof.
In some embodiments of formula (I), m is 0; R.sub.1 is halogen; n
is any integer of 1-4; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is alkylene-R.sub.6 wherein R.sub.6 is NR.sub.aR.sub.b,
C.sub.5-7heterocyclic ring having 0 to 3 hetero atoms selected from
O, N and S; or C.sub.10-12 fused heterocyclic ring having 0 to 3
hetero atoms selected from O, N and S; and R.sub.a and R.sub.b are
alkyl.
In some embodiments of formula (I), m is 0; R.sub.1 is halogen; n
is any integer of 1-2; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is (CH.sub.2).sub.1-4R.sub.6 wherein R.sub.6 is
unsubstituted or substituted pyrrolidinyl, oxolanyl, thiolanyl,
pyrrolyl, furanyl, thiophenyl, piperidinyl, oxanyl, thianyl,
morpholinoyl, pyridinyl, piperidinyl, piperazinyl, thiopyranyl,
pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl; benzimidazolyl;
pyrazolyl; indazolyl; pyrazolyl; quinolinyl; indolyl; indazolyl;
azaindolyl; azaindazolyl; deazapurinyl; or indanyl.
In some embodiments of formula (I), m is 0; R.sub.1 is halogen; n
is any integer of 1-2; R.sub.3 is H; X is C(O); R.sub.4 is H;
R.sub.5 is (CH.sub.2).sub.1-4R.sub.6 wherein R.sub.6 is
unsubstituted or substituted pyrrolidinyl, morpholinoyl, pyridinyl,
piperidinyl, piperazinyl, or indolyl.
In some embodiments of formula (I), m is 0; R.sub.1 is C.sub.1; n
is 1; R.sub.3 is H, x is C(O); R.sub.4 is H R.sub.5 is
CH.sub.2CH.sub.2N(CH.sub.3).sub.2, pyrrolidinyl substituted by
ethyl, or CH.sub.2N(CH.sub.2CH.sub.3).sub.2.
In some embodiments formula (I), the compounds include but not
limited to the following:
##STR00004## m is 0; R.sub.3 is H; X is C(O); and R is
##STR00005##
TABLE-US-00001 Example (Compound #) Code Number R.sub.1
(CH.sub.2).sub.n Structure of R Example 25 (27) MPT0L102 19-1717 Cl
CH.sub.2 ##STR00006## Example 41 (43) MPT0L122 19-1935 Cl CH.sub.2
##STR00007## Example 42 (44) MPT0L123 19-1936 Cl CH.sub.2
##STR00008## Example 43 (45) MPT0L132 Cl CH.sub.2 ##STR00009##
Example 44 (46) MPT0L133 Cl CH.sub.2 ##STR00010## Example 45 (47)
MPT0L134 Cl CH.sub.2 ##STR00011## Example 46 (48) MPT0L136 Cl
CH.sub.2 ##STR00012## Example 47 (49) MPT0L137 Cl CH.sub.2
##STR00013##
In some embodiments of formula (I), the compound is selected from
the group consisting of:
##STR00014## or a tautomer or stereoisomer thereof, or a solvate,
prodrug or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compounds having the
following Formula (II):
##STR00015## wherein Y is --N--, --N--(CH.sub.2).sub.n-- or
--NC(O)--; m is an integer of 0-4; R.sub.1 is halogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, NH.sub.2,
NO.sub.2, OH or CN; each R.sub.2 is the same or different,
representing H, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, NH.sub.2, NO.sub.2, C.sub.1-10alkyloxy,
C.sub.1-10alkylamino, C.sub.1-10alkyloxyC.sub.1-10alkyl, OH or CN,
C.sub.6-10aryl or C.sub.5-7heterocyclic having 1 to 3 heteroatoms
selected from the group consisting of N, O and S; R.sub.3 is H,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, NH.sub.2,
NO.sub.2, OH, CN or R.sub.3 together with R.sub.7 forms a
heterocyclic ring; and R.sub.7 is aryl unsubstituted or substituted
by one to five of OH, halogen, NH.sub.2, NO.sub.2, CN, alkyl,
alkenyl, alkynyl, alkyloxy, aryl, --NHSO.sub.2aryl wherein aryl is
unsubstituted or substituted by alkyloxy, OH, halogen, NH.sub.2,
NO.sub.2, CN, alkyl, alkenyl, alkynyl, alkylthio, alkylamino,
alkyloxyalkyl, or heteroaryl unsubstituted or substituted by alkyl,
alkenyl, alkynyl, OH, halogen, CN, NH.sub.2 or NO.sub.2;
heterocyclic ring unsubstituted or substituted by alkyloxy, OH,
halogen, NH.sub.2, NO.sub.2, CN, alkyl, alkenyl, alkynyl,
alkylthio, alkylamino, alkyloxyalkyl, --SO.sub.2aryl unsubstituted
or substituted by alkyloxy, OH, halogen, NH.sub.2, NO.sub.2, CN,
alkyl, alkenyl, alkynyl, alkylthio, alkylamino or alkyloxyalkyl, or
--C(O)aryl unsubstituted or substituted by one to five of OH,
halogen, NH.sub.2, NO.sub.2, CN, alkyl, alkenyl, alkynyl, alkyloxy
or aryl; or fused heterocyclic ring unsubstituted or substituted by
alkyloxy, OH, halogen, NH.sub.2, NO.sub.2, CN, alkyl, alkenyl,
alkynyl, alkylthio, alkylamino, alkyloxyalkyl, --SO.sub.2aryl
unsubstituted or substituted by alkyloxy, OH, halogen, NH.sub.2,
NO.sub.2, CN, alkyl, alkenyl, alkynyl, alkylthio, alkylamino or
alkyloxyalkyl; or a tautomer or stereoisomer thereof, or a solvate,
prodrug or a pharmaceutically acceptable salt thereof.
In one embodiment of formula (II), m is 0; R.sub.1 is halogen; Y is
--N--; R.sub.3 is H or C.sub.1-10alkyl; and R.sub.7 is phenyl
unsubstituted or substituted by one to five halogen,
C.sub.1-10alkyloxy, --N(H)S(O.sub.2)phenyl unsubstituted or
substituted by C.sub.1-10alkyloxy or C.sub.1-10alkylpiperazinyl;
quinolinyl, indolyl or indolinyl unsubstituted or substituted by
--S(O.sub.2)phenyl substituted by C.sub.1-10alkyloxy.
In one embodiment of formula (II), m is 0; R.sub.1 is halogen; Y is
a bond; and R.sub.3 together with R.sub.7 forms a isoindolinyl.
In one embodiment of formula (II), m is 0; R.sub.1 is halogen; Y is
--NC(O)-- or --N--(CH.sub.2).sub.1-4, R.sub.3 is H; and R.sub.7 is
phenylC.sub.1-4alkoxy or piperazinylC.sub.1-10alkyl.
In one embodiment of formula (II), m is 0; R.sub.1 is halogen; Y is
a --N-- or --N--(CH.sub.2).sub.1-4; R.sub.3 is H; and R.sub.7 is
indolinyl substituted by C(O)phenyl substituted by one to four OH
or C.sub.1-10alkyl.
In some embodiments formula (I), the compounds include but not
limited to the following:
##STR00016##
TABLE-US-00002 Example (Compound #) Code Number R6 R1 R2 R3 R4 R5
Example 92 MPT0L029 21-1062 H H H NHSO.sub.2Ph(p-OCH.sub.3) H H
(71) Example 94 MPT0L030 21-1080 H H NHSO.sub.2Ph(p-OCH.sub.3) H H
H (72) Example 97 MPT0L045 31-184 C.sub.2H.sub.5 H H F H H (75)
Example 98 MPT0L046 31-218 H H H 4-methylpiperazine- H H (76) l-yl
Example 99 MPT0L047 31-238 H H H 4-ethylpiperazine-l- H H (77) yl
Example 100 MPT0L048 19-1425-2A H F H I H H (78) Example 101
MPT0L049 19-1442 H Cl OCH.sub.3 Cl OCH.sub.3 Cl (79) Example 102
MPT0L050 19-1444 H CN H I H H (80)
##STR00017##
TABLE-US-00003 Example (Compound #) Code Number Structure of R
Example 103 (81) MPT0L026 31-158 ##STR00018## Example 104 (82)
MPT0L027 31-160 ##STR00019## Example 105 (83) MPT0L028 31-170
##STR00020## Example 106 (84) MPT0L032 21-1101 ##STR00021## Example
107 (85) MPT0L033 21-1102 ##STR00022## Example 108 (86) MPT0L035
21-1104B ##STR00023## Example 109 (87) MPT0L009 19-1217
##STR00024## Example 110 (88) MPTOL044 31-164 ##STR00025## Example
111 (89) MPT0L089 21-1242 ##STR00026##
##STR00027##
TABLE-US-00004 Example (Compound #) Code Number X Structure of R
Example 112 (90) MPT0L025 31-148 CO ##STR00028## Example 113 (91)
MPT0L078 31-376 CH2 ##STR00029## Example 114 (92) MPT0L077 31-398
CH2 ##STR00030##
The invention disclosed herein also encompasses prodrugs of the
disclosed compounds. Prodrugs are considered to be any covalently
bonded carriers that release an active compound of Formula (I) or
Formula (II) in vivo. Non-limiting examples of prodrugs include
esters of compounds of Formula (I) or Formula (II), and these may
be prepared by reacting such compounds with anhydrides such as
succinic anhydride.
The invention disclosed herein also encompasses pharmaceutically
acceptable salts of the disclosed compounds. In one embodiment, the
present invention includes any and all non-toxic, pharmaceutically
acceptable salts of the disclosed compounds, comprising inorganic
and organic acid addition salts and basic salts. The
pharmaceutically acceptable salts of the present invention can be
synthesized from the parent compound which contains a basic or
acidic moiety by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a sufficient amount of the appropriate base or
acid in water or in an organic diluent like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile, or a mixture thereof. For
example, such salts include acetates, ascorbates,
benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates,
bromides/hydrobromides, Ca-edetates/edetates, camsylates,
carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane
disulfonates, estolates esylates, fumarates, gluceptates,
gluconates, glutamates, glycolates, glycollylarsnilates,
hexylresorcinates, hydrabamines, hydroxymaleates,
hydroxynaphthoates, iodides, isothionates, lactates, lactobionates,
malates, maleates, mandelates, methanesulfonates, mesylates,
methylbromides, methylnitrates, methylsulfates, mucates,
napsylates, nitrates, oxalates, pamoates, pantothenates,
phenylacetates, phosphates/diphosphates, polygalacturonates,
propionates, salicylates, stearates subacetates, succinates,
sulfamides, sulfates, tannates, tartrates, teoclates,
toluenesulfonates, triethiodides, ammonium, benzathines,
chloroprocaines, cholines, diethanolamines, ethylenediamines,
meglumines and procaines. Further pharmaceutically acceptable salts
can be formed with cations from metals like aluminium, calcium,
lithium, magnesium, potassium, sodium, zinc and the like. (See
Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977),
66, 1-19.)
The invention disclosed herein also encompasses solvates of the
disclosed compounds. One type of solvate is a hydrate. Solvates
typically do not contribute significantly to the physiological
activity or toxicity of the compounds and as such can function as
pharmacological equivalents.
The invention disclosed herein also encompasses tautomers and
isomers of the disclosed compounds. A given chemical formula or
name shall encompass tautomers and all stereo, optical and
geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers
etc.) and racemates thereof as well as mixtures in different
proportions of the separate enantiomers, mixtures of diastereomers,
or mixtures of any of the foregoing forms where such isomers and
enantiomers exist, as well as salts, including pharmaceutically
acceptable salts thereof and solvates thereof such as for instance
hydrates including solvates of the free compounds or solvates of a
salt of the compound.
Preparation of the Compounds of the Invention
The compounds of the present invention can be prepared using
methods known to those skilled in the art in view of this
disclosure. For example, the preferred compounds of the invention
can be prepared as shown in the following schemes:
##STR00031##
##STR00032##
##STR00033##
##STR00034## Pharmaceutical Compositions and Treatments of the
Methods of the Invention
Accordingly, the compounds of the invention are potential targets
in treatment and/or prevention of neoplastic diseases,
neurodegenerative diseases, inflammatory diseases and/or metabolic
disorders. In some embodiments, the neoplastic disease includes but
is not limited to benign tumor and cancer. In some embodiments,
neurodegenerative disease includes but is not limited to ALS,
Parkinson's disease, Alzheimer's disease, and Huntington's disease.
In some embodiments, autoimmune and inflammatory disease includes
but is not limited to insulin-dependent diabetes mellitus (IDDM),
diabetes mellitus, multiple sclerosis, experimental autoimmune
encephalomyelitis, acute disseminated encephalomyelitis, arthritis,
rheumatoid arthritis, experimental autoimmune arthritis, myasthenia
gravis, thyroiditis, Hashimoto's disease, primary myxedema,
thyrotoxicosis, pernicious anemia, autoimmune atrophic gastritis,
Addison's disease, premature menopause, male infertility, juvenile
diabetes, goodpasture's syndrome, pemphigus vulgaris, pemphigoid,
sympathetic ophthalmia, phacogenic uveitis, autoimmune
haemolyticanaemia, idiopathic leucophenia, primary biliary
cirrhosis, active chronic hepatitis Hb.sub.s-ve, cryptogenic
cirrhosis, ulcerative colitis, Sjogren's syndrome, scleroderma,
Wegener's granulomatosis, poly/dermatomyositis, discoid LE,
systemic lupus erythematosus, chron's disease, psoriasis,
ankylosingspondylitisis, antiphospholipid antibody syndrome,
aplastic anemia, autoimmune hepatitis, coeliac disease, graves'
disease, guillain-barre syndrome (GBS), Idiopathic thrombocytopenic
purpura, opsoclonus myoclonus syndrome (OMS), optic neuritis, ORd's
thyroiditis, pemphigus, polyarthritis, primary biliary cirrhosis,
Reiter's syndrome, Takayasu's, temporal arteritis, warm autoimmune
hemolytic anemia, wegener's granulomatosis, alopecia universalis,
behcet's disease, chagas' disease, chronic fatigue syndrome,
dysautonomia, endometriosis, hidradenitis suppurativa, interstitial
cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative
colitis, vitiligo, vulvodynia, inflammatory skin diseases, allergic
contact dermatitis, H. pylori gastritis, chronic nasal inflammatory
disease, arteriosclerosis and graft versus host disease. In some
embodiments, metabolic disorder includes but is not limited to
diabetes, high blood pressure, cholesterol, elevated triglyceride
level, impaired fasting glucose and insulin resistance.
The compound of the invention is present in the composition in an
amount which is effective to treat a particular disorder, including
cancers, Parkinson's disease, Alzheimer's disease, and Huntington's
disease, restenosis, inflammation, rheumatoid arthritis,
inflammatory disorder, tissue injury due to inflammation,
hyperproliferative diseases, severe or arthritic psoriasis,
muscle-wasting diseases, chronic infectious diseases, abnormal
immune response, conditions involving vulnerable plaques, injuries
related to ischemic conditions, and viral infection and
proliferation.
The compound of the present invention may be administered to a
mammal in the form of a raw chemical without any other components
present. The compound is preferably administered as part of a
pharmaceutical composition containing the compound combined with a
suitable pharmaceutically acceptable carrier. Such a carrier can be
selected from pharmaceutically acceptable excipients, diluents and
auxiliaries.
Pharmaceutical compositions within the scope of the present
invention include all compositions where a compound of the present
invention is combined with a pharmaceutically acceptable carrier.
In a preferred embodiment, the compound is present in the
composition in an amount that is effective to achieve its intended
therapeutic purpose. While individual needs may vary, a
determination of optimal ranges of effective amounts of each
compound is within the skill of the art. Typically, the compounds
may be administered to a mammal, e.g. a human, at a dose of from
about 0.1 to about 100 mg per kg body weight of the mammal, or an
equivalent amount of a pharmaceutically acceptable salt, prodrug or
solvate thereof, per day to treat, prevent or ameliorate the
particular disorder. Preferably, the dose ranges from about 0.1 to
about 90 mg, about 0.1 to about 80 mg, about 0.1 to about 70 mg,
about 0.1 to about 60 mg, about 0.1 to about 50 mg, about 0.1 to
about 40 mg, about 0.1 to about 30 mg, about 0.1 to about 20 mg,
about 0.1 to about 10 mg, about 0.1 to about 5 mg, about 0.5 to
about 100 mg, about 0.5 to about 90 mg, about 0.5 to about 80 mg,
about 0.5 to about 70 mg, about 0.5 to about 60 mg, about 0.5 to
about 50 mg, about 0.5 to about 40 mg, about 0.5 to about 30 mg,
about 0.5 to about 20 mg, about 0.5 to about 10 mg, about 0.5 to
about 5 mg, about 1 to about 100 mg, about 1 to about 90 mg, about
1 to about 80 mg, about 1 to about 70 mg, about 1 to about 60 mg,
about 1 to about 50 mg, about 1 to about 40 mg, about 1 to about 30
mg, about 1 to about 20 mg, about 1 to about 10 mg, about 5 to
about 100 mg, about 5 to about 90 mg, about 5 to about 80 mg, about
5 to about 70 mg, about 5 to about 60 mg, about 5 to about 50 mg,
about 5 to about 40 mg, about 5 to about 30 mg, about 5 to about 20
mg, about 5 to about 10 mg, about 10 to about 100, about 20 to
about 100, about 30 to about 100, about 40 to about 100, about 50
to about 100, about 60 to about 100, about 70 to about 100, about
80 to about 100, about 5 to about 90, about 10 to about 90, about
10 to about 80, about 10 to about 70, about 10 to about 60, about
10 to about 50, about 10 to about 40, about 10 to about 30, about
20 to about 90, about 20 to about 80, about 20 to about 70, about
20 to about 60, about 20 to about 50, about 20 to about 40, about
30 to about 90, about 30 to about 80, about 30 to about 70, about
30 to about 60, about 30 to about 50, about 40 to about 90, about
40 to about 80, about 40 to about 60, about 50 to about 90, about
50 to about 80, about 50 to about 70 per kg body weight of the
mammal, or an equivalent amount of a pharmaceutically acceptable
salt, prodrug or solvate thereof, per day. A useful oral dose of a
compound of the present invention administered to a mammal is from
about 1 to about 100 mg per kg body weight of the mammal (the
preferred dose is as mentioned above), or an equivalent amount of
the pharmaceutically acceptable salt, prodrug or solvate thereof.
For intramuscular injection, the dose is typically about one-half
of the oral dose.
A unit oral dose may comprise from about 5 to about 100 mg, and
preferably about 5 to about 100 mg of a compound. The unit dose can
be administered one or more times daily, e.g. as one or more
tablets or capsules, each containing from about 0.01 mg to about 50
mg of the compound, or an equivalent amount of a pharmaceutically
acceptable salt, prodrug or solvate thereof.
The compounds of the present invention may be useful in combination
with one or more second therapeutic agents, particularly
therapeutic agents suitable for the treatment and/or prevention of
the conditions and diseases presented previously.
For example in the cancer treatment, the second therapeutic agent
can be a mitotic inhibitor (such as a taxane (preferably paclitaxel
or docetaxel), vinca alkaloid (preferably, vinblastine,
vincristine, vindesine orvinorelbine) and vepesid; an anthracycline
antibiotic (such as doxorubicin, daunorubicin, daunorubicin,
epirubicin, idarubicin, valrubicin ormitoxantrone); a nucleoside
analog (such as gemcitabine); an EGFR inhibitor (such as gefitinib
and erlotinib); an folate antimetabolite (such as trimethoprim,
pyrimethamine or pemetrexed); cisplatin or carboplatin. Examples of
the second therapeutic agent include but are not limited to
tamoxifen, taxol, vinblastine, etoposide (VP-16), adriamycin,
5-fluorouracil (5FU), camptothecin, actinomycin-D, mitomycin C,
combretastatin(s), more particularly docetaxel (taxotere),
cisplatin (CDDP), cyclophosphamide, doxorubicin, methotrexate,
paclitaxel and vincristine, and derivatives and prodrugs
thereof.
Further useful second therapeutic agents include compounds that
interfere with DNA replication, mitosis, chromosomal segregation
and/or tubulin activity. Such compounds include adriamycin, also
known as doxorubicin, etoposide, verapamil, podophyllotoxin(s),
combretastatin(s) and the like. Agents that disrupt the synthesis
and fidelity of polynucleotide precursors may also be used.
Particularly useful are agents that have undergone extensive
testing and are readily available. As such, agents such as
5-fluorouracil (5-FU) are preferentially used by neoplastic tissue,
making this agent particularly useful for targeting neoplastic
cells.
The term "angiogenesis" refers to the generation of new blood
vessels, generally in a tissue or organ. Under normal physiological
conditions, humans or animals undergo angiogenesis only in specific
restricted situations. Uncontrolled (persistent and/or unregulated)
angiogenesis is related to various disease states, and occurs
during tumor development and metastasis. Accordingly, the
anti-angiogenesis agent also can be used as the second anti-cancer
agent. Other second anti-cancer agents include but are not limited
to alkylators such as cyclophosphamide, edelfosine, estramustine
and melphalan; antimetabolites such as fluorouracil, methotrexate,
mercaptopurine, UFT, tegafur, uracil and cytarabine; anti-tumor
Bleomycin, daunorubicin, doxorubicin and epirubicin; antibiotics
such as mitomycin and mitoxantrone; topoisomerase such as
camptothecin, irinotecan, etoposide, topotecan; taxanes docetaxel,
paclitxael, vinca alkaloids, vinblastine, vincristine, cisplatin
and octreotide.
Histone deacetylase inhibitors (HDAC inhibitors) also can be used
as the second therapeutic agent. Examples include but not limited
to hydroxamic acids (or hydroxamates), such as trichostatin A,
cyclic tetrapeptides (such as trapoxin B), and depsipeptides,
benzamides, electrophilic ketones, and aliphatic acid compounds
such as phenylbutyrate and valproic acid.
For example in inflammation treatment, the second therapeutic agent
includes, but is not limited to, corticosteroid, a lubricant, a
keratolytic agent, a vitamin D.sub.3 derivative, PUVA and
anthralin, .beta..sub.2-agonist and a corticosteroid.
For example in autoimmune disease treatment, the second therapeutic
agent includes, but is not limited to, immunosuppressants, NSAIDs,
COX-2 inhibitors, biologics, non-steroidal calcineurin inhibitors,
steroidal anti-inflammatory agents, 5-amino salicylic acid, DMARDs,
hydroxychloroquine sulfate, inflammatory modulators, agents that
interfere with B cell action, and penicillamine.
Pharmaceutically acceptable carriers and/or diluents are familiar
to those skilled in the art. For compositions formulated as liquid
solutions, acceptable carriers and/or diluents include saline and
sterile water, and may optionally include antioxidants, buffers,
bacteriostats and other common additives. The compositions can also
be formulated as pills, capsules, granules, or tablets which
contain, in addition to a compound of the invention, diluents,
dispersing and surface active agents, binders, and lubricants. One
skilled in this art may further formulate the compound of the
invention in an appropriate manner, and in accordance with accepted
practices, such as those disclosed in Remington's Pharmaceutical
Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.
In one aspect, the present invention provides a method for treating
a disease in association with block of ubiquitination-proteasome
system in a subject, comprising administering to the subject an
effective amount of the compound of the invention. The disease
includes but is not limited to cancer and related conditions as
discussed above. Accordingly, first, the invention provides a
method for treating a cancer in a subject, comprising administering
to the subject an effective amount of the compound of the
invention. Such method includes administering a compound of the
present invention to a subject in an amount sufficient to treat the
condition. For example, the cancers include but are not limited to
the group consisting of: neuroblastoma; lung cancer; bile duct
cancer; non small cell lung carcinoma; hepatocellular carcinoma;
head and neck squamous cell carcinoma; squamous cell cervical
carcinoma; lymphoma; nasopharyngeal carcinoma; gastric cancer;
colon cancer; uterine cervical carcinoma; gall bladder cancer;
prostate cancer; breast cancer; testicular germ cell tumors;
colorectal cancer; glioma; thyroid cancer; basal cell carcinoma;
gastrointestinal stromal cancer; hepatoblastoma; endometrial
cancer; ovarian cancer; pancreatic cancer; renal cell cancer,
Kaposi's sarcoma, chronic leukemia, sarcoma, rectal cancer, throat
cancer, melanoma, colon cancer, bladder cancer, mastocytoma,
mammary carcinoma, mammary adenocarcinoma, pharyngeal squamous cell
carcinoma, testicular cancer, gastrointestinal cancer, or stomach
cancer and urothelial cancer.
In a further aspect, the present invention provides a method for
treating inflammatory disorders and autoimmune disorders and
related conditions as discussed above. Such methods include
administering a compound of the present invention to a subject in
an amount sufficient to treat the condition. Preferably, the
disorders are restenosis, inflammation, rheumatoid arthritis,
tissue injury due to inflammation, hyperproliferative diseases,
severe or arthritic psoriasis, muscle-wasting diseases, chronic
infectious diseases, abnormal immune response, conditions involving
vulnerable plaques, injuries related to ischemic conditions, and
viral infection or proliferation.
The dose range of the compounds of general formula (I) applicable
per day is usually from 5 to 100 mg, preferably from 5 to 100 mg
per kg body weight of the patient. Each dosage unit may
conveniently contain from 5 to 100 mg of a compound according to
the invention.
The actual therapeutically effective amount or therapeutic dosage
will of course depend on factors known by those skilled in the art
such as age and weight of the patient, route of administration and
severity of disease. In any case, the combination will be
administered at dosages and in a manner which allow a
therapeutically effective amount to be delivered based upon
subject's unique condition.
For oral administration, suitable pharmaceutical compositions of
the invention include powders, granules, pills, tablets, lozenges,
chews, gels, and capsules as well as liquids, syrups, suspensions,
elixirs, and emulsions. These compositions may also include
anti-oxidants, flavorants, preservatives, suspending, thickening
and emulsifying agents, colorants, flavoring agents and other
pharmaceutically acceptable additives. Formulations for oral
administration may be formulated to be immediate release or
modified release, where modified release includes delayed,
sustained, pulsed, controlled, targeted and programmed release.
For parenteral administration, the compounds of the present
invention are administered directly into the blood stream, into
muscle, or into an internal organ via an intravenous,
intraarterial, intraperitoneal, intramuscular, subcutaneous or
other injection or infusion. Parenteral formulations may be
prepared in aqueous injection solutions which may contain, in
addition to the compound of the invention, buffers, antioxidants,
bacteriostats, salts, carbohydrates, and other additives commonly
employed in such solutions. Parenteral administrations may be
immediate release or modified release (such as an injected or
implanted depot).
Compounds of the present invention may also be administered
topically, (intra)dermally, or transdermally to the skin or mucosa.
Typical formulations include gels, hydrogels, lotions, solutions,
creams, ointments, dressings, foams, skin patches, wafers, implants
and microemulsions. Compounds of the present invention may also be
administered via inhalation or intranasal administration, such as
with a dry powder, an aerosol spray or as drops. Additional routes
of administration for compounds of the present invention include
intravaginal and rectal (by means of a suppository, pessary or
enema), and ocular and aural.
Biological Assay
Blocking of ITCH Self-Ubiquitination
The compounds of the invention and a control compound (such as
Compound 44 of WO 2010/005534) as a comparative compound were used
to test the blocking of ITCH self-ubiquitination. The results show
that the compounds of the invention blocks ITCH self-ubiquitination
(Lys-dependent) more efficiently than the control compound (see
FIG. 1). [Reference for in vitro assay: Scialpi F, Malatesta M,
Peschiaroli A, Rossi M, Melino G, and Bernassola F. Itch
self-polyubiquitylation occurs through lysine-63 linkages. Biochem
Pharmacol. 2008 Dec. 1; 76(11):1515-21. Reference for in vivo
assay: Chang L, Kamata H, Solinas G, Luo J L, Maeda S, Venuprasad
K, Liu Y C, and Karin M. The E3 ubiquitin ligase itch couples JNK
activation to TNFalpha-induced cell death by inducing c-FLIP(L)
turnover. Cell. 2006 Feb. 10; 124(3):601-13.]
Antiproliferative Activity Against Human Normal and Cancer Cell
Lines Using Growth inhibition assay (GI.sub.50)
The compounds of the invention were subjected to growth inhibition
assay. Cells were seeded in 96-well plastic plates and exposed to
MPT0L132, MPT0L133, and MPT0L134 for 48 hours. Cell viability was
assessed using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
Growth inhibition was expressed as the percentage of surviving
cells in drug-treated versus DMSO-treated control cells. The
results are shown as follows.
TABLE-US-00005 HL-60 HCT-116 MDA-MB-231 Hep3B IC.sub.50 (.mu.M)
GI.sub.50 (.mu.M) Compounds Mean .+-. S.E. Mean .+-. S.E. MPT0L132
2.50 .+-. 0.15 3.69 .+-. 0.24 10~30 10~30 MPT0L133 1.67 .+-. 0.27
4.04 .+-. 0.65 10~30 10~30 MPT0L134 2.52 .+-. 0.12 3.53 .+-. 0.24
10~30 10~30
Effects of the Compounds of the Invention on IL-6 Production in
murineRAW264.7 Macrophage Cells
Cell Culture.
The RAW264.7 mouse macrophage cells were purchased from the
Bioresource Collection and Research Center (Hsinchu, Taiwan) and
the cells cultured at 37.degree. C. in 5% CO2/95% air in,
respectively, 90% Ham's F-12 or Dulbecco's modified Eagle medium,
both containing 10% heat-inactivated fetal bovine serum (FBS)
(Invitrogen Life Technologies, Carlsbad, Calif.) and 1%
penicillin/streptomycin (Biological Industries, Israel).
IL-6 Determination.
To determine the effect of MPT0L 132, MPT0L133 and MPT0L134 on the
production of cytokine IL-6 from LPS-stimulated cells, RAW 264.7
cells (1.times.10.sup.6) were plated and pretreated in the presence
or absence of MPT0L 132, MPT0L133 and MPT0L134 for 1 h, and then
stimulated with LPS (25 ng/mL) for 24 h at 37.degree. C.
Supernatants were collected and the concentrations of cytokines
IL-6 was measured by ELISA kit.
Effects of the Compounds of the Invention on IL-6 Production in
Human RAFLS (Rheumatoid Arthritis Fibroblast-Like Synoviocyte)
Cells
Cell Culture.
Human rheumatoid arthritis fibroblast-like synoviocytes (RAFLS)
from Cell Application Inc. (San Diego, Calif., USA) were grown in
synoviocyte growth medium from the same supplier.
IL-6 Determination.
RA-FLS (2.5.times.10.sup.4) was treated with various concentrations
of MPT0L132, MPT0L133 and MPT0L134 for 24 h, then the medium was
collected and assayed for IL-6 using commercial ELISA kit.
The Compounds of the Invention Inhibit Development of Arthritis in
an Adjuvant-Induced Arthritis (AIA) Model
In Vivo Adjuvant-Induced Arthritis (AIA) Model.
Five-week-old male Lewis rats were obtained from the National
Laboratory Animal Center (Taipei, Taiwan). Complete Freund's
adjuvant (CFA) was prepared by suspending heat-killed Mycobacterium
butyricum (Difco) in mineral oil at 3 mg/mL. CFA-induced arthritis
was induced by intradermal injection of 100 .mu.L of the CFA
emulsion into the base of the right hind paw on day 0. MPT0L132,
MPT0L133 and MPT0L134 (each for 25 mg/kg, po, qd), Bortezomib (1
mg/kg, ip, qwk), positive control indomethacin (1 mg/kg, po, qwk),
or vehicle was given by gavage from day 2 to day 21. On days 0, 2,
6, 9, 13, 17, and 21, the animals were weighed and both hind paw
volumes measured using a digital plethysmometer (Diagnostic &
Research Instruments Co. Ltd, Taipei, Taiwan). On day 21,
micro-computed tomography (micro-CT) of the paws was performed by
the Core Facilities Center of the National Research Program for
Biopharmaceuticals using an in vivo micro-CT scanner (Skyscan 1176,
Bruker Corp., Kontich, Belgium) at 18 .mu.m resolution and
180.degree. scanning with a rotation step of 0.8o per image, 300
msec integration time, 70 keV photon energy, and 350 .mu.A
current.
Treatment with the Compounds of the Invention to Prevent Bone
Mineral Density (BMD) and Bone Mineral Content (BMC) Loss in AIA
Model
Quantification of volumetric bone mineral density (BMD) and bone
volume (BV) was performed in a defined bone area ranging 12 mm from
tarsals to the end of the calcaneus. The bone mineral content (BMC)
was described by the product of BV and BMD.
EXAMPLES
Example 25
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(pyridin-4-ylmethyl)benzamide (27)
##STR00035##
A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol),
DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a
while, to which was then added 4-aminomethylpyridine (0.13 ml, 1.32
mmol) at room temperature and stirred overnight. The residue was
purified by flash column over silica gel
(dichloromethane:methanol=9:1, Rf=0.48) to afford 27 (0.31 g,
81.57%) as a red solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6):
.delta. 4.47 (d, J=6.0 Hz, 2H), 5.01 (s, 1H), 7.28 (d, J=5.7 Hz,
2H), 7.41 (d, J=8.1 Hz, 2H), 7.75 (t, J=6.3 Hz, 1H), 7.80-7.87 (m,
3H), 7.97 (d, J=7.8 Hz, 2H), 8.08 (s, 1H), 8.48 (d, J=6.0 Hz, 2H),
9.08 (t, J=6.0 Hz, 1H).
Example 41
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-morpholinoethyl)benzamide (43)
##STR00036##
A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol),
DIPEA (0.13 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a
while, to which was then added 2-morpholinoethanamine (0.17 ml,
1.32 mmol) at room temperature, and the mixture was stirred
overnight. The residue was filtered by suction filtration to yield
a red product. The residue was without further purification to
afford 43 (0.23 g, 57.58%) as a red solid. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. 2.38-2.45 (m, 6H), 3.54 (s, 4H), 4.99 (s,
2H), 7.36 (d, J=8.1 Hz, 2H), 7.71-7.84 (m, 4H), 7.96 (d, J=7.5 Hz,
2H), 8.05 (s, 1H), 8.33 (t, J=5.1 Hz, 1H).
Example 42
N-(2-(1H-indol-3-yl)ethyl)-4-(((3-chloro-1,4-dioxo-1,4-dihydron-
aphthalen-2-yl)amino)methyl)benzamide (44)
##STR00037##
A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol),
DIPEA (0.13 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a
while, to which was then added tryptamine (0.21 g, 1.32 mmol) at
room temperature and stirred overnight. The residue was purified by
flash column over silica gel (ethyl acetate:n-hexane=2:1, Rf=0.45)
to afford 44 (0.13 g, 30.53%) as a red solid. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. 2.72-2.94 (m, 2H), 3.47-3.54 (m, 2H), 4.99
(s, 2H), 6.92-6.98 (m, 1H), 7.01-7.07 (m, 1H), 7.15 (d, J=2.4 Hz,
1H), 7.31 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.55 (d, J=7.5
Hz, 1H), 7.73-7.82 (m, 4H), 7.96 (d, J=8.1 Hz, 2H), 8.06 (s, 1H),
8.54 (t, J=5.7 Hz, 1H), 10.78 (s, 1H).
Example 43
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(dimethylamino)ethyl)benzamide (45)
##STR00038##
A mixture of 97 (0.30 g, 0.88 mmol), EDC.HCl (0.25 g, 1.32 mmol),
HOBt (0.14 g, 1.06 mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml)
was stirred for a while, to which was then added
2-dimethylaminoethylamine (0.12 ml, 1.06 mmol) at room temperature
and stirred overnight. The residue was purified by flash column
over silica gel (dichloromethane:methanol=9:1, Rf=0.33) to afford
45 (0.05 g, 13.79%) as a red solid. .sup.1H-NMR (300 MHz,
CD.sub.3OD): .delta. 2.92 (s, 6H), 3.72 (t, J=6.0 Hz, 2H), 5.10 (s,
2H), 7.44 (d, J=8.4 Hz, 2H), 7.68-7.81 (m, 2H), 7.85 (d, J=8.4 Hz,
2H), 8.02-8.06 (m, 2H).
Example 44
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide (46)
##STR00039##
A mixture of 97 (0.30 g, 0.88 mmol), EDC.HCl (0.25 g, 1.32 mmol),
HOBt (0.14 g, 1.06 mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml)
was stirred for a while, to which was then added
2-(pyrrolidin-1-yl)ethanamine (0.13 ml, 1.06 mmol) at room
temperature and stirred overnight. The residue was purified by
flash column over silica gel (dichloromethane:methanol=9:1,
Rf=0.33) to afford 46 (0.22 g, 57.09%) as a red solid. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6): .delta. 1.89 (s, 4H), 3.22-3.25 (m, 5H),
3.54-3.60 (m, 3H), 5.00 (t, J=7.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H),
7.72-7.82 (m, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.94-7.98 (m, 2H), 8.08
(t, J=7.2 Hz, 1H), 8.74 (t, J=5.7 Hz, 1H).
Example 45
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(diethylamino)ethyl)benzamide (47)
##STR00040##
A mixture of 97 (0.30 g, 0.88 mmol), EDC.HCl (0.25 g, 1.32 mmol),
HOBt (0.14 g, 1.06 mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml)
was stirred for a while, to which was then added
2-diethylaminoethylamine (0.15 ml, 1.06 mmol) at room temperature
and stirred overnight. The residue was purified by flash column
over silica gel (dichloromethane:methanol=9:1, Rf=0.30) to afford
47 (0.06 g, 15.50%) as a red solid. .sup.1H-NMR (300 MHz,
CD.sub.3OD): .delta. 1.33 (t, J=7.2 Hz, 6H), 3.32-3.38 (m, 3H),
3.73 (t, J=6.0 Hz, 2H), 5.10 (s, 2H), 7.45 (d, J=8.1 Hz, 2H),
7.67-7.80 (m, 2H), 7.85 (d, J=8.1 Hz, 2H), 8.02-8.06 (m, 2H).
Example 46
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(piperidin-1-yl)ethyl)benzamide (48)
##STR00041##
Example 46
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(piperidin-1-yl)ethyl)benzamide (48)
A mixture of 97 (0.30 g, 0.88 mmol), EDC.HCl (0.25 g, 1.32 mmol),
HOBt (0.14 g, 1.06 mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml)
was stirred for a while, to which was then added
2-(piperidin-1-yl)ethanamine (0.15 ml, 1.06 mmol) at room
temperature and stirred overnight. The residue was purified by
flash column over silica gel (dichloromethane:methanol=9:1,
Rf=0.55) to afford 48 (0.08 g, 20.11%) as a red solid. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6): .delta. 1.42-1.44 (m, 2H), 1.58-1.60 (m,
4H), 2.78 (br, 6H), 3.44-3.48 (m, 2H), 4.99 (d, J=7.2 Hz, 2H), 7.37
(d, J=8.4 Hz, 2H), 7.71-7.84 (m, 4H), 7.94-7.97 (m, 2H), 8.07 (t,
J=7.2 Hz, 1H), 8.53 (br, 1H).
Example 47
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl-
)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide (49)
##STR00042##
A mixture of 97 (0.30 g, 0.88 mmol), EDC.HCl (0.25 g, 1.32 mmol),
HOBt (0.14 g, 1.06 mmol), NMM (0.23 ml, 2.11 mmol) and DMF (2.5 ml)
was stirred for a while, to which was then added
2-(4-methylpiperazin-1-yl)ethylamine (0.16 ml, 1.06 mmol) at room
temperature and stirred overnight. The residue was purified by
flash column over silica gel (dichloromethane:methanol=9:1,
Rf=0.19) to afford 49 (0.08 g, 19.47%) as a red solid. .sup.1H-NMR
(300 MHz, DMSO-d.sub.6): .delta. 2.13 (s, 3H), 2.36-2.42 (br, 12H),
4.91 (d, J=6.3 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.67-7.77 (m, 4H),
7.88 (d, J=6.9 Hz, 2H), 7.98 (br, 1H), 8.25 (br, 1H).
Example 92
N-(4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)phen-
yl)-4-methoxybenzenesulfonamide (71)
##STR00043##
Compound 127 (0.1 g, 0.33 mmol) was dissolved in dichloromethane
(10 ml) and to which was then added triethylamine (0.01 ml, 0.07
mmol) and 4-methoxybenzenesulfonyl chloride (0.07 g, 0.34 mmol).
The reaction mixture was stirred at room temperature for 2 days.
The residue was purified by flash column over silica gel (ethyl
acetate:n-Hexane=1:2, Rf=0.14) to afford 71 (0.01 g, 6.68%) as a
red solid. .sup.1H-NMR (500 MHz, d-Acetone): .delta. 3.85 (s, 3H),
7.01 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz,
2H), 7.69 (d, J=8.5 Hz, 2H), 7.79-7.86 (m, 2H), 8.08 (d, J=9.0 Hz,
2H).
Example 93 2-((3-aminophenyl)amino)-3-chloronaphthalene-1,4-dione
(73)
##STR00044##
A mixture of 2,3-dichloro-1,4-naphthoquinone (2.14 g, 9.43 mmol)
and benzene-1,3-diamine (1.50 g, 9.25 mmol) and ethanol (25 mL) was
refluxed overnight. The solution was evaporated to give a residue,
which was purified by flash column over silica gel
(EtOAc:n-hexane=1:2, Rf=0.33) to afford 73 (0.90 g, 32.57%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 6.39 (s, 1H),
7.09-7.16 (m, 1H), 7.61 (brs, 1H), 7.66-7.83 (m, 3H), 8.10-8.15 (m,
1H), 8.17-8.22 (m, 2H).
Example 94
N-(3-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)phen-
yl)-4-methoxybenzenesulfonamide (72)
##STR00045##
Compound 73 (0.1 g, 0.33 mmol) was dissolved in dichloromethane (5
ml) and to which was then added triethylamine (0.01 ml, 0.07 mmol)
and 4-methoxybenzenesulfonyl chloride (0.07 g, 0.34 mmol). The
reaction mixture was stirred at room temperature for 2 days. The
residue was purified by flash column over silica gel (ethyl
acetate:n-Hexane=1:2, Rf=0.19) to afford 72 (0.01 g, 6.68%) as a
red solid. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.85 (s, 3H),
6.51 (brs, 1H), 6.82-6.92 (m, 5H), 7.21 (t, J=8.4 Hz, 1H), 7.56 (s,
1H), 7.68-7.73 (m, 3H), 7.78 (t, J=7.5 Hz, 1H), 8.12 (d, J=7.5 Hz,
1H), 8.18 (d, J=7.5 Hz, 1H).
Example 96 2-chloro-3-((4-fluorophenyl)amino)naphthalene-1,4-dione
(128)
##STR00046##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.20 mmol)
and 4-fluoroaniline (0.43 ml, 4.40 mmol) and ethanol (5 ml) was
refluxed for 16 h. The reaction mixture was filtered and washed by
dichloromethane, ethyl acetate and methanol. The residue was
without further purification to afford 128 (0.20 g, 30.30%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.15-7.17 (m, 4H),
7.77-7.89 (m, 2H), 8.03 (d, J=7.8 Hz, 2H), 9.29 (s, 1H).
Example 97
2-Chloro-3-(ethyl(4-fluorophenyl)amino)naphthalene-1,4-dione
(75)
##STR00047##
Compound 128 (0.20 g, 0.66 mmol) was dissolved in DMF (1 mL) and
added NaH (0.04 g, 0.86 mmol) then stirred for while and to which
was then added iodoethane (0.08 ml, 0.99 mmol) slowly at 0.degree.
C. The reaction mixture was warmed to room temperature, and
stirring was continued for another 1 h. The residue was purified by
flash column over silica gel (EtOAc:n-hexane=1:9) to afford
compound 75 (0.01 g, 4.59%). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 1.32 (t, J=6.9 Hz, 3H), 3.92 (q, J=7.2 Hz, 2H), 6.86-6.89
(m, 2H), 6.98-7.01 (m, 2H), 7.68-7.78 (m, 2H), 7.99-8.02 (m, 1H),
8.16-8.19 (m, 1H).
Example 98
2-Chloro-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)naphthalene-
-1,4-dione (76)
##STR00048##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.37 g, 1.60 mmol)
and 4-(4-methylpiperazin-1-yl)aniline (0.3 g, 1.46 mmol) was
dissolved in EtOH (5 ml). The reaction mixture was stirred and
refluxed for 16 h. The residue was purified by flash column over
silica gel (dichloromethane:methanol=29:1) to afford 76 (0.12 g,
21.52%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.36 (s, 3H),
2.58 (t, J=6.0 Hz, 4H), 3.23 (t, J=6.0 Hz, 4H), 6.88 (d, J=9.0 Hz,
2H), 7.01 (d, J=8.7 Hz, 2H), 7.65-7.77 (m, 3H), 8.10 (d, J=7.5 Hz,
1H), 8.18 (d, J=7.5 Hz, 1H).
Example 99
2-Chloro-3-((4-(4-ethylpiperazin-1-yl)phenyl)amino)naphthalene--
1,4-dione (77)
##STR00049##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.37 g, 1.60 mmol)
and 4-(4-ethylpiperazin-1-yl)aniline (0.3 g, 1.46 mmol) was
dissolved in EtOH (5 ml). The reaction was stirred and refluxed for
16 h. The residue was purified by flash column over silica gel
(dichloromethane:methanol=29:1) to afford 77 (0.10 g, 17.30%).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.15 (t, J=6.0 Hz, 3H),
2.48 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 4H), 3.26 (t, J=6.0 Hz,
4H), 6.89 (d, J=9.0 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 7.65-7.70 (m,
2H), 7.77-7.79 (m, 1H), 8.10-8.13 (m, 1H), 8.18-8.20 (m, 1H).
Example 100
2-chloro-3-((2-fluoro-4-iodophenyl)amino)naphthalene-1,4-dione
(78)
##STR00050##
A mixture of 2,3-dichloro-1,4-naphthaquinone (0.20 g, 0.88 mmol)
and 2-fluoro-4-iodoaniline (0.19 g, 0.80 mmol) was dissolved in
EtOH (15 ml) and stirred and refluxed for 3 day. The residue was
purified by flash column over silica gel (ethyl
acetate:n-Hexane=1:9, Rf=0.25) to afford 78 (0.08 g, 23.39%) as a
red solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. 7.09 (t,
J=8.4 Hz, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 7.83 (m, 2H), 8.01 (m,
2H), 9.22 (br, 1H).
Example 101
2-chloro-3-((2,4,6-trichloro-3,5-dimethoxyphenyl)amino)naphthalene-1,4-di-
one (79)
##STR00051##
A mixture of 2,3-dichloro-1,4-naphthaquinone (0.20 g, 0.88 mmol),
potassium carbonate (0.17 g, 1.20 mmol) and
2,4,6-chloro-3,5-methoxyaniline (0.21 g, 0.80 mmol) was dissolved
in DMF (2 ml) and stirred at 120.degree. C. overnight. The residue
was purified by flash column over silica gel (ethyl
acetate:n-Hexane=1:15, Rf=0.15) to afford 79 (0.18 g, 50.32%) as a
yellow solid. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 3.93 (s,
6H), 7.31 (s, 1H), 7.76 (m, 2H), 8.15 (m, 1H), 8.19 (m, 1H).
Example 102
2-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-5-iodobenzonitri-
le (80)
##STR00052##
A mixture of 2,3-dichloro-1,4-naphthaquinone (0.20 g, 0.88 mmol),
potassium carbonate (0.17 g, 1.20 mmol) and
2-amino-5-iodobenzonitrile (0.20 g, 0.80 mmol) was dissolved in DMF
(2 ml) and stirred at 120.degree. C. overnight. The residue was
purified by flash column over silica gel (ethyl
acetate:n-Hexane=1:9, Rf=0.05) to afford 80 (0.15 g, 43.14%) as a
yellow solid. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 6.80 (s,
1H), 7.60 (s, 1H), 7.79 (m, 3H), 7.94 (m, 1H), 8.17 (m, 1H), 8.20
(m, 1H).
Example 103 2-Chloro-3-((quinolin-6-yl)amino)naphthalene-1,4-dione
(81)
##STR00053##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.20 mmol)
and 6-aminoquinoline (0.63 g, 4.40 mmol) was dissolved in ethanol
(5 ml). The reaction mixture was refluxed for 16 h. The residue was
filtered and washed by dichloromethane, ethyl acetate and methanol.
The product was without more purification to afford 81 (0.38 g,
51.60%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.50 (q,
J=4.2 Hz, 1H), 7.56-7.62 (m, 2H), 7.79-7.93 (m, 3H), 8.03 (q, J=7.5
Hz, 2H), 8.26 (d, J=7.5 Hz, 1H), 8.78-8.80 (m, 1H).
Example 104 2-Chloro-3-(quinolin-3-ylamino)naphthalene-1,4-dione
(82)
##STR00054##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.20 mmol)
and 3-aminoquinoline (0.63 g, 4.40 mmol) was dissolved in ethanol
(5 ml). The reaction mixture was refluxed for 16 h. The residue was
filtered and washed by dichloromethane, ethyl acetate and methanol.
The product was without more purification to afford 82 (0.31 g,
42.09%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.57 (t,
J=7.2 Hz, 1H), 7.64-7.69 (m, 1H), 7.77-7.91 (m, 4H), 7.97 (d, J=8.1
Hz, 1H), 8.00-8.04 (m, 2H).
Example 105 2-Chloro-3-(quinolin-5-ylamino)naphthalene-1,4-dione
(83)
##STR00055##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.20 mmol)
and 5-aminoquinoline (0.63 g, 4.40 mmol) was dissolved in ethanol
(5 ml). The reaction mixture was refluxed for 16 h. The residue was
filtered and washed by dichloromethane, ethyl acetate and methanol.
The product was without more purification to afford 83 (0.46 g,
62.46%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.24-7.27 (m,
1H), 7.48 (q, J=4.2 Hz, 1H), 7.68-7.82 (m, 4H), 8.08 (d, J=9.0 Hz,
1H), 8.15-8.22 (m, 2H), 8.33-8.36 (m, 1H), 8.97-8.98 (m, 1H).
Example 106 2-((1H-indol-6-yl)amino)-3-chloronaphthalene-1,4-dione
(84)
##STR00056##
Compound-6-nitroindole (0.30 g, 1.85 mmol) was dissolved in ethanol
(10 ml) and added the 10% Pd/C as catalyst. The reaction was
stirred at room temperature for 2 hr. The residue was filtered and
without more purification to get the product. To the product was
dissolved in ethanol (20 ml) and added
2,3-dichloro-1,4-naphthoquinone (0.42 g, 1.85 mmol). The reaction
mixture was refluxed for 0.5h. The residue was purified by flash
column over silica gel (ethyl acetate:n-Hexane=1:3, Rf=0.25) to
afford 84 (0.15 g, 25.12%) as a red solid. .sup.1H NMR (300 MHz,
d-Acetone): .delta. 6.49 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 7.29 (s,
1H), 7.36 (t, J=3.0 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.79-7.92 (m,
2H), 8.10-8.20 (m, 2H), 8.58 (s, 1H), 10.31 (s, 1H).
Example 107 2-((1H-indol-5-yl)amino)-3-chloronaphthalene-1,4-dione
(85)
##STR00057##
A mixture of 5-nitroindole (0.50 g, 3.08 mmol) was dissolved in
ethanol (10 ml) and added the 10% Pd/C as catalyst. The reaction
was stirred at room temperature for 3 hr. The residue was filtered
and without more purification to get the product. To the product
was dissolved in ethanol (10 ml) and added
2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.20 mmol). The reaction
mixture was refluxed for 1 h. The residue was purified by flash
column over silica gel (ethyl acetate:n-Hexane=1:3, Rf=0.28) to
afford 85 (0.15 g, 21.13%) as a red solid. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 6.55-6.57 (m, 1H), 7.02 (dd, J=2.1, 8.7 Hz,
1H), 7.29 (t, J=3.0 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.41-7.42 (m,
1H), 7.66-7.72 (m, 1H), 7.75-7.81 (m, 1H), 7.86 (s, 1H), 8.14 (d,
J=6.3 Hz, 1H), 8.21 (d, J=6.6 Hz, 1H), 8.26 (s, 1H).
Example 108
2-chloro-3-((1-((4-methoxyphenyl)sulfonyl)indolin-5-yl)amino)naphthalene--
1,4-dione (86)
##STR00058##
A mixture of 5-nitroindole (0.50 g, 3.08 mmol) was dissolved in DMF
(3 mL) and added NaH (0.15 g, 3.75 mmol) then stirred for a while,
to which was then added 4-methoxybenzenesulfonyl chloride (0.64 g,
3.08 mmol) and stirred for 0.5 hr. The residue was quenched with
water and extracted by dichloromethane (30 ml*3). The residue was
purified by flash column over silica gel (ethyl
acetate:n-hexane=1:3, Rf=0.31) to get the white product. Then the
white product (0.16 g, 0.48 mmol) was dissolved in MeOH (10 ml) and
stirred under H.sub.2 for 1 h. The residue was without further
purification and dissolved in EtOH (15 ml). To the reaction mixture
was added 2,3-dichloro-1,4-naphthaquinone (0.06 g, 0.26 mmol) and
stirred and refluxed for 1 hr. The residue was filtered and
purified by flash column over silica gel (ethyl
acetate:n-hexane=1:2, Rf=0.08) to afford 86 (0.46 g, 50.46%) as a
red solid. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 2.86 (t,
J=8.7 Hz, 2H), 3.85 (s, 3H), 3.96 (t, J=8.4 Hz, 2H), 6.83 (d, J=8.7
Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 7.14 (d,
J=8.7 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.72 (d, J=9.0 Hz, 2H),
7.76-7.81 (m, 1H), 8.13 (d, J=6.6 Hz, 1H), 8.20 (d, J=7.2 Hz,
1H).
Example 109
2-chloro-3-((1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)amino)naphthalene--
1,4-dione (87)
##STR00059##
A mixture of 5-bromo-7-nitroindole (0.50 g, 2.07 mmol),
4-methoxybenzenesulfonyl chloride (0.64 g, 3.11 mmol), and pyridine
(3.0 ml) was stirred and refluxed overnight. The residue was
purified by flash column over silica gel (ethyl
acetate:n-hexane=1:2, Rf=0.35) to get the yellow product. Then the
yellow product was dissolved in MeOH (5 ml) and under H.sub.2 and
40 psi for overnight. The residue was without further purification
to afford as a black solid. A mixture of residue (0.51 g, 1.68
mmol) and 2,3-dichloro-1,4-naphthaquinone (0.40 g, 1.76 mmol) was
dissolved in EtOH (15 ml) and stirred and refluxed for 3 day. The
residue was filtered and purified by flash column over silica gel
(ethyl acetate:n-hexane=1:4, Rf=0.15) to afford 87 (0.46 g, 50.46%)
as a red solid. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 2.22
(t, J=7.5 Hz, 2H), 3.79 (s, 3H), 3.92 (t, J=7.5 Hz, 2H), 6.97 (d,
J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 1H), 7.15
(t, J=8.0 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.82 (t, J=7.5 Hz, 1H),
7.88 (t, J=8.5 Hz, 1H), 8.04 (m, 2H), 9.38 (s, 1H).
Example 110 2-Chloro-3-(quinolin-8-ylamino)naphthalene-1,4-dione
(88)
##STR00060##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.50 g, 2.2 mmol) and
8-aminoquinoline (0.63 g, 4.40 mmol) was dissolved in ethanol (5
ml). The reaction mixture was refluxed for 16 h. The residue was
filtered and washed by dichloromethane, ethyl acetate and methanol.
The product was without more purification to afford 88 (0.35 g,
47.52%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.54 (d, J=7.5
Hz, 1H), 7.64-7.78 (m, 4H), 7.94-7.97 (m, 2H), 8.05 (t, J=9.0 Hz,
2H), 8.86 (d, J=8.7 Hz, 1H), 9.17 (s, 1H).
Example 111 2-chloro-3-(isoindolin-2-yl)naphthalene-1,4-dione
(89)
##STR00061##
A mixture of 2,3-dichloro-1,4-naphthoquinone (0.34 g, 1.50 mmol)
and isoindoline (0.30 g, 2.52 mmol) was dissolved in ethanol (10
ml). The reaction mixture was refluxed for overnight. The residue
was filtered and without more purification to afford 89 (0.23 g,
49.50%) as a red solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6):
7.28-7.31 (m, 2H), 7.37-7.40 (m, 2H), 7.71-7.74 (m, 1H), 7.77-7.80
(m, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H).
Example 112
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methoxybenzamide
(90)
##STR00062##
A mixture of p-anisoyl chloride (0.49 ml, 3.61 mmol) was added
slowly to the corresponding 2-amino-3-chloro-1,4-naphthoquinone
(0.50 g, 2.4 mmole) and NaH (0.15 g, 3.61 mmol) in DMF (3 ml) at
0.degree. C. The reaction mixture was warmed to room temperature,
and stirring was continued for another 1 h. The residue was
purified by flash column over silica gel (EtOAc:n-hexane=1:2) to
afford 90 (0.04 g, 4.88%) as a red solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 3.84 (s, 3H), 7.08 (d, J=9.0 Hz, 2H),
7.89-7.92 (m, 2H), 7.99 (d, J=8.7 Hz, 2H), 8.03-8.05 (m, 1H),
8.06-8.12 (m, 1H), 10.27 (s, 1H).
Example 113
2-chloro-3-((4-(4-methylpiperazin-1-yl)benzyl)amino)naphthalene-1,4-dione
(91)
##STR00063##
A mixture of 4-(4-methylpiperazin-1-yl)benzaldehyde (1.0 g, 4.90
mmol), t-butylcarbamate (1.72 g, 14.69 mmol), triethylsilane (1.56
ml, 9.79 mmol) was dissolved in acetonitrile (21 ml) and TFA (0.75
ml). The reaction mixture was stirred at room temperature under
N.sub.2 for overnight. The mixture was washed with saturated
NaHCO.sub.3 (aq.) and saturated NaCl (aq.) and worked up. To the
residue, TFA (3.1 ml) was added and the stirred for 2 hr. The
reaction was quenched with saturated NaHCO.sub.3 (aq.) and an
extraction was conducted with dichloromethane. The residue was
dissolved in ethanol (10 ml) and to which
2,3-dichloro-1,4-naphthoquinone (0.82 g, 3.60 mmol) were added, and
the mixture was refluxed for overnight. The reaction was purified
by flash column over silica gel (dichloromethane:methanol=30:1) to
afford 91 (0.10 g, 5.16%) as a purple solid. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 2.36 (s, 3H), 2.59 (t, J=5.1 Hz, 4H), 3.24 (t,
J=5.4 Hz, 4H), 4.97 (d, J=6.0 Hz, 2H), 6.13 (brs, 1H), 6.94 (d,
J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.63 (t, J=7.5 Hz, 1H), 7.74
(t, J=7.5 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 8.17 (d, J=7.5 Hz,
1H).
Example 114
2-chloro-3-((4-(4-ethylpiperazin-1-yl)benzyl)amino)naphthalene-1,4-dione
(92)
##STR00064##
A mixture of 4-(4-ethylpiperazin-1-yl)benzaldehyde (1.50 g, 6.87
mmol), t-butylcarbamate (2.41 g, 20.61 mmol), triethylsilane (2.2
ml, 13.74 mmol) was dissolved in acetonitrile (29.3 ml) and TFA
(1.05 ml). The reaction mixture was stirred at room temperature
under N.sub.2 overnight. The mixture was washed with saturated
(aq.) and saturated NaCl (aq.) and worked up. To the residue, TFA
(4.4 ml) was added and the stirred for 2 hr. The reaction was
quenched with saturated NaHCO.sub.3 (aq.) and an extraction was
conducted with dichloromethane. The residue was dissolved in
ethanol (10 ml) and to which 2,3-dichloro-1,4-naphthoquinone (0.95
g, 4.20 mmol) were added, and the mixture was refluxed overnight.
The reaction was purified by flash column over silica gel
(dichloromethane:methanol=30:1) to afford 92 (0.08 g, 2.84%) as a
purple solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.13 (t,
J=4.5 Hz, 3H), 2.47 (q, J=4.5 Hz, 2H), 2.60 (t, J=3.0 Hz, 4H), 3.23
(t, J=3.0 Hz, 4H), 4.95 (d, J=3.6 Hz, 2H), 6.13 (brs, 1H), 6.92 (d,
J=5.1 Hz, 2H), 7.22 (d, J=5.1 Hz, 2H), 7.61 (t, J=5.1 Hz, 1H), 7.72
(t, J=5.4 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H), 8.15 (d, J=4.8 Hz,
1H).
* * * * *